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[ THE SCIENCE OF MEDICINE S T E V E N NO V E L L A Steven Novella, MD, is assistant professor of neurology at Yale School of Medicine, the host of the Skeptics’ Guide to the Universe podcast, author of the NeuroLogica blog, executive editor of the Science-Based Medicine blog, and president of the New England Skeptical Society.

The Poor, Misunderstood Placebo

recent study looking into the ef- panding health claims within an in- course. For any variable symptom, peri- fects of acupuncture on relieving creasingly unregulated market. ods of time when symptoms are at their A back pain was widely re ported in worst are likely, by chance alone, to be Operational Definition of Placebo the media as finding that “acupuncture followed by a return to more average works, even fake acupuncture.” Behind In the context of research, the “placebo symptoms. the headlines, the authors were more effect” has a very specific operational Other artifacts include the biases of circumspect in the paper it self, con- definition: it is the treatment effect the researchers and the subjects. Re - cluding: measured in the placebo arm of a clin- searchers want their interventions to Although acupuncture was found ef - ical trial, which includes those subjects work and may therefore bias their as- fective for chronic low back pain, tai- who have received a fake or inert treat- sessments to be more positive. Subjects loring needling sites to each patient ment. If a trial is rigorously designed, want to receive an effective treatment and penetration of the skin appear to placebo effects should include every- and to meet the expectations of the re- be unimportant in eliciting therapeu- thing other than a physiological re- searcher. They want to justify their risk, tic benefits. These findings raise ques- sponse to a biologically active treat ment. expense (even if it’s just time), and their tions about acupuncture’s purported mechanisms of action. It remains un- Therefore, we can subtract placebo-ef- decision to receive a treatment or enter clear whether acupuncture or our fect findings from the treatment group, a trial. Conditioning, in which one asso- simulated method of acupuncture who will display treatment effects plus ciates a treatment ritual with feeling provide physiologically important placebo ef fects, and we are left with a better, is another related placebo effect. stimulation or represent placebo or measurement of the treatment effect There are also a number of nonspe- nonspecific ef fects. (Cherkin et al. 2009) alone. cific effects, such as the well-docu- This simple but effective logic is the mented observer effect (also called the The authors compared acupuncture cornerstone of medical research. It is Hawthorne effect), in which the very fact to placebo acupuncture (creating the necessary because there are a variety of of being observed in a clinical trial re- sensation of acupuncture with tooth- effects that can create the false impres- sults in a change in behavior and re- picks that do not penetrate the skin) sion that a treatment is working even porting (McCarney et al. 2007). People and found no difference. When a drug when it isn’t. It is a mistake to assume are more likely to be compliant with is compared with a placebo and there is that the only relevant false impression treatment, take better care of themselves, no difference in the response, the stan- is a “mind over matter” effect resulting and get regular medical attention as part dard conclusion is that the drug has no from belief in the treatment. This is not of a trial. Related to this is the cheerleader effect—it does not work. But that logic the case. effect: for any functional assessment, peo- is being turned on its head by what is Placebo Effects ple will tend to try harder if they are being called “placebo medicine,” in being encouraged, if they feel they which the placebo effect is seen as a Placebo effects fall into several cate- should be doing better, or if they have real, valuable, and desired outcome of gories: illusions of observation, bias, hope that the treatment is working. patient treatment (Novella 2009). nonspecific effects, and physiological ef- And finally there are real physiologi- Placebo effects (plural), however, are fects. Much of what is measured as a cal effects resulting from the ritual of varied and complex. For the most part placebo effect is, in fact, simply an illu- treatment. For example, treatment may they are not a biological response to the sion of the process of observation. These in volve relaxation or simply taking a expectation of benefit, which is what illusory effects include regression to the break from your otherwise hectic daily most people assume. Understanding mean, which is a statistical phenome- routine. Believing one is being treated placebo effects is critical to making non that includes extreme symptoms may reduce anxiety about the illness or sense of medical research and ever-ex- becoming less ex treme as a matter of symptoms, which in turn may reduce

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sympathetic activity, reduce blood pres- reporting relief; the augmented group trials, are mostly due to bias. Spe - sure and strain on the heart, and reduce (those who received placebo acupunc- cifically, significant placebo effects were the levels of stress hormones. Hands- ture plus enhanced interaction with the found only for subjectively reported on treatments have the benefit of therapist) reported a drop of over eighty symptoms. Further, the size of this ef- human contact, which improves mood points, with over 60 percent of patients fect varied widely among trials. and provides an overall feeling of well- reporting relief. Conclusion being. It’s very interesting that the group The perception of pain in particular that received no intervention, not even Increasingly, placebo effects are being is subject to these nonspecific effects, a placebo, still had a 30 percent re- used to justify the use of ineffective and such as when an improved mood re - sponse. This response is likely entirely even inert treatments, with the assump- duces the perception of pain. In addi- due to observational artifacts (Haw - tion that “the” placebo effect is a true tion, conditioning, expectation, and thorne effect, etc.). The placebo inter- healing effect. What the research indi- nonspecific benefits may actually cause vention also led to an improved cates, however, is that there are many the release of natural endorphins that response—in this case, expectation and placebo effects, and they are mostly bias reduce pain transmission (Benedetti conditioning might be having an effect. and illusion—not real effects. There are 2007) or the release of dopamine in the The enhanced intervention group also nonspecific effects that are likely reward centers of the brain (de la showed the strongest effect, likely rep- valuable, but these effects can mostly be Fuente-Fernández and Stoessl 2004). resenting an increase in the nonspecific categorized as stress reduction and im- benefits of a positive therapeutic rela- Breaking It Down provement in mood through attention tionship. and encouragement. It should be re- Given this more thorough understand- Hróbjartsson and Gøtzsche have membered that any placebo effect ing of placebo effects, it is not reason- been studying placebo effects for years. worth having will also accompany a le- They recently reviewed clinical studies able to assume that the measured gitimate treatment that actually works. that contain a no-treatment arm as a placebo effect in a clinical trial is mostly On close inspection, placebo effects are way of measuring placebo effects. They or entirely a real “mind over matter” not a justification for substituting conclude: health benefit. Instead, the placebo ef- hocus-pocus for real medicine. n fect may consist mostly or entirely of il- We did not find that placebo inter- lusion and bias. One might ask, “Which ventions have important clinical ef- References kinds of effects are contributing to the fects in general. However, in certain Benedetti, F. 2007. Placebo and endogenous measured placebo effect of specific settings placebo interventions can in- mechanisms of analgesia. Handbook of Experi- fluence patient-reported outcomes, mental Pharmacology 177: 393–413. treatments?” The answer is that it de- especially pain and nausea, though it Cherkin, D.C., K.J. Sherman, A.L. Avins, J.H. pends on what is being treated. is difficult to distinguish patient-re- Erro, L. Ichikawa, W.E. Barlow, K. Delaney, For example, a study of placebo ef - ported effects of placebo from biased et al. 2009. A randomized trial comparing reporting. The effect on pain varied, acupuncture, simulated acupuncture, and fects in the treatment of irritable bowel usual care for chronic low back pain. Archives syndrome (Kaptchuk et al. 2008) found even among trials with low risk of bias, from negligible to clinically im- of Internal Medicine 169(9): 858–66. a substantial placebo effect in place with portant. Variations in the effect of De la Fuente-Fernández, R., and A.J. Stoessl. 2004. The biochemical bases of the placebo the use of placebo acupuncture. The placebo were partly explained by vari- effect. Science and Engineering Ethics 10(1): same study also found that the enhanced ations in how trials were conducted 143–50. placebo group—members of which re- and how patients were informed. Hróbjartsson, A., and P.C. Gøtzsche. 2010. (Hróbjartsson and Gøtzsche 2010) ceived placebo acupuncture with en- Placebo interventions for all clinical condi- tions. Cochrane Database Systematic Review hanced interaction between the Let’s break this down a bit. First, (1): CD003974. therapist and the subject—reported Hróbjartsson and Gøtzsche found that Kaptchuk, T.J., J.M. Kelley, L.A. Conboy, R.B. added “warmth, attention, and confi- when you look at any objective or clin- Davis, C.E. Kerr, E.E. Jacobson, I. Kirsch, et al. 2008. Components of placebo effect: Ran- dence.” After three weeks, the waiting- ically important outcome—the kinds of domised controlled trial in patients with irri- list group (those who received no things that would indicate a real bio- table bowel syndrome. British Medical Journal treatment—not even placebo) had about logical effect—there is no discernible 336(7651): 999–1003. a thirty-point drop on the symptom McCarney, R., J. Warner, S. Iliffe, R. van Haselen, placebo effect. That is, there is no M. Griffin, and P. Fisher. 2007. The severity scale, with almost 30 percent of “mind over matter” self-healing that Hawthorne Effect: A randomised, controlled patients reporting adequate relief; the can be attributed to the placebo effect. trial. BioMed Central Medical Research treatment group (those who received What the authors found is also most Methodology 7: 30. Novella, S.P. 2009. The rise of placebo medicine. placebo acupuncture) had a forty-two- compatible with the hypothesis that Available online at www.sciencebasedmedi- point drop, with 44 percent of patients placebo effects, as measured in clinical cine.org/?p=672.

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